{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:03:44Z","timestamp":1791475424151,"version":"4.3.4"},"reference-count":57,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T00:00:00Z","timestamp":1734566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Croatian Science Foundation","award":["UIP-2017-05-5160"],"award-info":[{"award-number":["UIP-2017-05-5160"]}]},{"name":"Croatian Science Foundation","award":["IP-2022-10-9829"],"award-info":[{"award-number":["IP-2022-10-9829"]}]},{"name":"Croatian Science Foundation","award":["KK.01.1.1.02.0021"],"award-info":[{"award-number":["KK.01.1.1.02.0021"]}]},{"name":"University of Zagreb","award":["UIP-2017-05-5160"],"award-info":[{"award-number":["UIP-2017-05-5160"]}]},{"name":"University of Zagreb","award":["IP-2022-10-9829"],"award-info":[{"award-number":["IP-2022-10-9829"]}]},{"name":"University of Zagreb","award":["KK.01.1.1.02.0021"],"award-info":[{"award-number":["KK.01.1.1.02.0021"]}]},{"name":"European Regional Development Fund, University of Zagreb","award":["UIP-2017-05-5160"],"award-info":[{"award-number":["UIP-2017-05-5160"]}]},{"name":"European Regional Development Fund, University of Zagreb","award":["IP-2022-10-9829"],"award-info":[{"award-number":["IP-2022-10-9829"]}]},{"name":"European Regional Development Fund, University of Zagreb","award":["KK.01.1.1.02.0021"],"award-info":[{"award-number":["KK.01.1.1.02.0021"]}]},{"name":"European Social Fund","award":["UIP-2017-05-5160"],"award-info":[{"award-number":["UIP-2017-05-5160"]}]},{"name":"European Social Fund","award":["IP-2022-10-9829"],"award-info":[{"award-number":["IP-2022-10-9829"]}]},{"name":"European Social Fund","award":["KK.01.1.1.02.0021"],"award-info":[{"award-number":["KK.01.1.1.02.0021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>As the resistance of Plasmodium to the existing antimalarials increases, there is a crucial need to expand the antimalarial drug pipeline. We recently identified potent antimalarial compounds, namely harmiquins, hybrids derived from the \u03b2-carboline alkaloid harmine and 4-amino-7-chloroquinoline, a key structural motif of chloroquine (CQ). To further explore the structure\u2212activity relationship, we synthesised 13 novel hybrid compounds at the position N-9 of the \u03b2-carboline ring and evaluated their efficacy in vitro against Plasmodium falciparum 3D7 and Dd2 strains (CQ sensitive and multi-drug resistant, respectively). All compounds exhibit persistent antimalarial activity against both strains of P. falciparum. The most interesting derivatives had low nanomolar activity against both strains (IC50 (33) = 4.7 \u00b1 1.3 nM against Pf3D7 and 6.5 \u00b1 2.5 nM against PfDd2; IC50 (37) = 4.6 \u00b1 0.6 nM against 3D7 and 10.5 \u00b1 0.4 nM against Dd2). Resistance indices (RIs) ranged from 0.9 to 5.3 compared to CQ (RI = 14.4), highlighting their superior consistency in activity against both strains. The cytotoxicity screening performed on HepG2 revealed over 3 orders of magnitude higher IC50 for most of the compounds, with SIs from 711.0 to 8081.8. Spectroscopic studies explored the affinities of newly synthesised compounds for DNA, RNA, and HSA. Both tested hybrids, 34 and 39, were intrinsically fluorescent in an aqueous medium, characterised by remarkable Stokes shifts of emission maxima (\u0394\u03bb = +103 and +93 nm for 34 and 39, respectively). Fluorimetric experiments revealed that compound 34, with its shorter and more flexible linker, exhibited at least an order of magnitude higher affinity toward ds-DNAs versus ds-RNA and two orders of magnitude higher affinity toward GC-DNAs compared to 39. The behaviour of the investigated compounds upon binding to HSA is very similar, showing a strong hypsochromic shift of the emission maximum (almost \u0394\u03bb = \u221270 nm) and demonstrating their effectiveness as fluorimetric probes for distinguishing between DNA\/RNA and proteins.<\/jats:p>","DOI":"10.3390\/molecules29245991","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T06:50:44Z","timestamp":1734591044000},"page":"5991","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Towards Novel Antiplasmodial Agents\u2014Design, Synthesis and Antimalarial Activity of Second-Generation \u03b2-Carboline\/Chloroquine Hybrids"],"prefix":"10.3390","volume":"29","author":[{"given":"Ana","family":"Penava","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kova\u010di\u0107a 1, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4868-4031","authenticated-orcid":false,"given":"Marina","family":"Marinovi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kova\u010di\u0107a 1, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lais Pessanha","family":"de Carvalho","sequence":"additional","affiliation":[{"name":"Institute of Tropical Medicine, University of T\u00fcbingen, Wilhelmstra\u00dfe 27, 72074 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7970-1429","authenticated-orcid":false,"given":"Jana","family":"Held","sequence":"additional","affiliation":[{"name":"Institute of Tropical Medicine, University of T\u00fcbingen, Wilhelmstra\u00dfe 27, 72074 T\u00fcbingen, Germany"},{"name":"Partner Site T\u00fcbingen, German Center for Infection Research (DZIF), 72074 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9933-446X","authenticated-orcid":false,"given":"Ivo","family":"Piantanida","sequence":"additional","affiliation":[{"name":"Rudjer Bo\u0161kovi\u0107 Institute, Bijeni\u010dka cesta 54, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0657-1635","authenticated-orcid":false,"given":"Dijana Pavlovi\u0107","family":"Safti\u0107","sequence":"additional","affiliation":[{"name":"Rudjer Bo\u0161kovi\u0107 Institute, Bijeni\u010dka cesta 54, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zrinka","family":"Raji\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kova\u010di\u0107a 1, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Perkovi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kova\u010di\u0107a 1, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1016\/S0140-6736(18)30324-6","article-title":"Malaria","volume":"391","author":"Ashley","year":"2018","journal-title":"Lancet"},{"key":"ref_2","unstructured":"By-Nc-Sa, C. (2023). World Malaria Report 2023, World Health Organization."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1038\/s41467-022-30133-w","article-title":"Malaria in 2022: Increasing Challenges, Cautious Optimism","volume":"13","author":"Jagannathan","year":"2022","journal-title":"Nat. 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